Glycerol-rich vesicular matrices as an effective oral platform for valsartan: Box-Behnken optimization and ex vivo/in vivo evaluation

The current work aims to evaluate the efficacy of glycerol-rich vesicular matrices for enhancing the oral bioavailability and antihypertensive capacity of valsartan (VAL), a poorly soluble medication. These vesicular dispersions were generated employing the thin film hydration technique and optimized through the Box-Behnken design to investigate the effect of cholesterol, phospholipid, and glycerol concentrations on the vesicle size (VS), entrapment efficiency (EE), and drug release after 6 h (%Q_6h). The optimized formulation (0.46%w/v cholesterol, 4.47% w/v phospholipid, and 10.12% w/v glycerol) exhibited nano-sized vesicles of 172.76 ± 6.47 nm with a narrow size distribution (PDI = 0.185 ± 0.101), a zeta potential of -42.4 ± 0.85 mV, an EE of 80.87 ± 1.58%, and a Q_6h of 96.68 ± 1.92%. Additionally, the physical mixture of optimized components in glycerol hydration medium showed a powerful synergistic solubility enhancement, which aligns with carrier-mediated hydration, thereby facilitating the dissolution of over 71% of the target drug load during processing. Morphological characterization using SEM and TEM unveiled spherical, non-aggregated vesicular matrices. FTIR studies confirmed the absence of chemical interactions between the drug and the formulation components, while DSC and XRD analyses evidenced the loss of crystalline character of valsartan upon vesicular incorporation. Ex vivo permeation of the ultra-elastic formulation displayed a flux value (135.07 ± 7.8 µg/cm² h) twice that of the plain drug. Furthermore, the optimized colloidal dispersion remained stable for three months under refrigerated and ambient conditions. Finally, in vivo investigations in dexamethasone-induced hypertensive rabbits showed a significant reduction in mean arterial pressure and a two-fold increase in systemic bioavailability compared to the unprocessed medication. Consequently, the developed vesicular colloidal delivery system holds significant potential for improving valsartan's oral therapeutic delivery.